The goal of this project is to investigate the feasibility of treating drug-sensitive and multidrug resistant (MDR) cancers, which overexpress folate receptors (FR) using engineered pH-sensitive micelles. Our results demonstrated that 1) doxorubicin (DOX) loaded micelles were equally cytotoxic to sensitive MCF-7 (breast) and A2780 (ovarian) cancer cells and their MDR counterparts , 2) micelle formulations were cytotoxic to MDR cell lines with various unicellular MDR mechanisms (including Pgp, MRP, LRP, topoisomerase II, and bcl-2), 3) the formulations caused tumor regression of both MDR breast and ovarian tumor xenografts in a mouse model, 4) polymer cytotoxicity and apparent systemic toxicity were not observed. The mechanisms involved in these effects are three-fold: 1) active internalization via FR-mediated endocytosis, 2) pH-triggered release of DOX in endosomes and 3) endosomal membrane disruption caused by the polymeric components. These sequential events avoid ATP-driven efflux pumps, allow high cytosolic DOX concentrations and minimize drug sequestration/exocytosis. These combined effects overwhelm multifactorial defense mechanisms presented by MDR cells. In an effort to bring us closer to our long-term goal of clinical application, this renewal application intends to present the scale-up of polymer and micelles production, the development of paclitaxel loaded micelles in Part I, the evaluation of two micelle formulations (doxorubicin and paclitaxel) against resistant breast cancer and ovarian cancer tumors for preclinical studies in Part II, and formulation testing using more clinically relevant multidrug resistant cell or tissue models while considering the intracellular and intratumoral pharmacokinetics.